A Novel Resuscitation for Hemorrhagic Shock: AM/AMBP-1

项目描述：该SBIR II期提案旨在进一步开发一种新的治疗药物， 抢救严重创伤失血性休克患者的方法。大多数创伤死亡 由于失血过多导致的组织灌注不足，或 炎症、感染和复苏后重要器官损伤。临床管理 出血性休克依赖于大量和快速的输液来维持血压。但 大多数严重失血的受害者对液体恢复反应不佳。的发展 因此，迫切需要用于创伤性失血复苏的有效策略。市场 仅在美国，出血治疗的潜力估计为> 100亿美元/年。我们最近 发现血管对肾上腺髓质素（AM）的反应性， 肽，在大鼠出血后降低，这通过其新的结合蛋白（即， AMBP-1）。用大鼠AM加AMBP-1治疗减少了在哺乳动物后的组织损伤和炎症反应。 出血和大容量复苏，表明AM/AMBP-1可能是一种有益的治疗方法 人类创伤的方法。阻碍AM/AMBP-1作为治疗剂开发的一个障碍 出血性休克的最大危险是大鼠蛋白在人体内的潜在免疫原性。因此，主要 我们的I期计划的目的是确定人AM/AMBP-1对出血的作用， 引起器官损伤、炎症和死亡。我们已经实现了这一里程碑使用啮齿动物模型， 重度失血性休克血压稳定第一阶段项目的结果表明， 人AM/AMBP-1的有效性，从而确立了II期研究的技术优点和可行性。 项目剂量-反应研究表明，在研究中提出的人AM/AMBP-1的最高剂量为100 mg/kg。 一期工程取得了较好的出血后保护效果。然而， 商业化的人AMBP-1限制了其进一步发展。为了克服这一障碍，我们必须 以低得多的成本成功地从人血清中分离和纯化AMBP-1。因此，我们继续 假设给予人AM/AMBP-1，即使在低容量复苏的情况下， 严重失血后的存活率在第二阶段的提案中，我们计划扩大人类 AMBP-1，进行额外的功效研究，确定人类的最佳保护剂量 AM/AMBP-1在出血中的作用，并进行药代动力学表征和毒理学评价。在 为了将该技术推进到临床试验，研究了人AM/AMBP-1在临床上更有效的作用。 将研究不受控制的出血的相关模型。我们的最终目标是发展商业 利用人AM/AMBP-1作为创伤受害者安全有效的复苏方法， 严重失血，特别是在遥远的战场环境中用于战斗伤员护理。

PROJECT DESCRIPTION: This SBIR Phase II proposal is intended to further develop a novel therapeutic approach to save the lives of severely injured trauma victims with hemorrhagic shock. Most trauma deaths result either from insufficient tissue perfusion due to excessive blood loss, or the development of inflammation, infection, and vital organ damage following resuscitation. Clinical management of hemorrhagic shock relies on massive and rapid infusion of fluids to maintain blood pressure. However, the majority of victims with severe blood loss do not respond well to fluid restoration. The development of effective strategies for resuscitation of traumatic blood loss, therefore, is urgently needed. The market potential for hemorrhage treatment is estimated at >$10 billion/year in the US alone. We have recently discovered that vascular responsiveness to adrenomedullin (AM), a newly-discovered potent vasoactive peptide, decreases after hemorrhage in the rat, which is markedly improved by its novel binding protein (i.e., AMBP-1). Treatment with rat AM plus AMBP-1 reduces tissue injury and inflammatory responses after hemorrhage and large volume resuscitation, suggesting that AM/AMBP-1 may be a beneficial treatment approach in human trauma. One obstacle hampering development of AM/AMBP-1 as a therapeutic agent for hemorrhagic shock is the potential immunogenicity of rat proteins in humans. Accordingly, the primary objective of our Phase I proposal was to determine the effect of human AM/AMBP-1 on hemorrhage- induced organ injury, inflammation, and mortality. We have achieved this milestone using a rodent model of severe hemorrhagic shock with fixed blood pressure. The results of the Phase I project demonstrated the efficacy of human AM/AMBP-1, and thereby established the technical merit and feasibility of the Phase II project. The dose-response study showed that the highest dose of human AM/AMBP-1 proposed in the Phase I project achieved a better protection after hemorrhage. However, the extremely high cost of commercial human AMBP-1 limits its further development. To overcome this obstacle, we have successfully isolated and purified AMBP-1 from human serum at a much lower cost. We therefore continue to hypothesize that administration of human AM/AMBP-1, even with low volume resuscitation, improves survival after severe blood loss. In this Phase II proposal, we plan to scale up the production of human AMBP-1, conduct additional efficacy studies determining the optimal protective dosage of human AM/AMBP-1 in hemorrhage, and perform pharmacokinetic characterization and toxicological evaluation. In order to advance the technology to clinical trials, the efficacy of human AM/AMBP-1 in more clinically relevant models of uncontrolled hemorrhage will be studied. Our ultimate goal is to develop the commercial utilization of human AM/AMBP-1 as a safe and effective resuscitation approach for the trauma victim with severe blood loss, especially for the use in combat casualty care at the far-forward battlefield setting.